One of the many pathologic obstacles of spinal cord repair following percussive trauma is the formation of a fluid-filled cyst across which regenerating axons have to traverse in order to reinnervate their distal targets. To this end, in a previously published study, we examined and demonstrated the potential use of electrospinning to engineer an implantable polarized matrix for axonal guidance. Nevertheless, it is recognized that successful spinal cord injury (SCI) therapies require a multifaceted approach of bridging the lesion site as well as providing trophic support, directional guidance cues, and neutralizing growth- inhibitory compounds so as to maximize the potential for axonal regrowth and functional recovery. In view of that, we propose a novel approach of incorporating into electrospun guidance matrices pharmacologic agents that can promote neuronal survival and neutralize inhibitory proteins associated with the gliotic scar. Specifically, in Aim 1, we plan to use in vitro studies to assess the extent to which these trophic factors, guidance cues, and neutralizing enzymes can be effectively electrospun into matrices to influence neuritic outgrowth. Subsequently, in Aim 2, we plan to surgically implant and test these enhanced matrices in a rat model of complete transection SCI. Histological and behavioral experiments will be employed to determine the extent of axonal regeneration and functional improvement, respectively. Collectively, the results of the proposed studies should lead to the development of a single interventional strategy that facilitates robust axon regeneration following SCI with concomitant improvements in functional recovery. PUBLIC HEALTH RELEVANCE: More than 250,000 Americans are currently living with spinal cord injury (SCI), a disability that causes untold physical, emotional, and financial hardship for both the patient and the family. It is recognized that successful SCI therapies require a multifaceted approach of bridging the injury site as well as providing trophic support, directional guidance cues, and neutralizing regeneration- inhibitory compounds so as to maximize the potential for neuronal regrowth and functional recovery. This proposal describes a novel approach of generating implantable electrospun matrices that is incorporated with therapeutic agents with the above properties and subsequently testing these matrices in a rat model of SCI.